Cerebrospinal fluid (CSF) circulation is essential for removing neuroinflammatory proteins through a process that involves the brain's newly discovered lymphatic system. Circulating CSF also delivers growth factors that help regulate brain development. Aberrant CSF circulation can result in a pathogenic buildup of neuroinflammatory proteins and alter brain growth. CSF serves to link the central nervous and immune systems, which are dysfunctional in neurodevelopmental disorders (NDDs). In three independent cohorts, our team was the first to report that children with idiopathic autism spectrum disorder (iASD) have increased CSF volume surrounding the brain (extra-axial CSF; EA-CSF) from 6 months to 4 years of age (Shen et al., 2013; 2017; 2018). Excessive EA-CSF was detectable at 6 months of age (prior to onset of the defining behavioral symptoms of ASD), was correlated with severity of specific later symptoms, and predicted later diagnosis. We extended this research to single-gene NDDs with varying degrees of overlapping and distinct symptoms with iASD and now present preliminary data showing that these single-gene NDDs also have excessive EA-CSF volume. Our preliminary data also indicate that rodent models of these NDDs have excessive EA-CSF, similar to the patient populations, and reduced CSF circulation. Our new observations suggest that excessive EA-CSF may be a potential biomarker of a shared pathophysiological process in multiple NDDs. This project will prospectively study infant cohorts of multiple NDDs, and corresponding mouse models, to examine the overarching hypothesis that excessive EA-CSF volume and impaired CSF circulation result in an accumulation of neuroinflammatory proteins and are related to aberrant brain and behavior development. This proposal will:  leverage resources from ongoing NIH-funded MRI studies of children with NDDs;  enlist a multidisciplinary team with expertise in CSF abnormalities in children with NDDs, neurophysiology of NDD mouse models, mouse neuroimaging, infant neuroimaging, clinical phenotyping of infants with NDDs, and the lymphatic system; and  utilize all three UNC IDDRC research cores to address the following aims:
Aim 1 : To elucidate potential mechanisms underlying excessive EA-CSF in selected NDD model mice.
Aim 2 : To examine relationships between EA-CSF volume, CSF circulation, and brain and behavior features in children with etiologically-distinct NDDs. This research will expand our knowledge of a new phenomenon ? aberrant CSF physiology in the early development of NDDs ? by examining the mechanisms and brain and behavior correlates in NDDs and corresponding rodent models, to provide important insights for: development of targeted treatments, potential predictive biomarkers of later disease progression, and knowledge about CSF pharmacodynamics relevant to upcoming clinical trials in NDDs using intrathecal CSF drug delivery. 1